N-heterocyclic Carbene Precatalyst Research Articles

Air-stable, well-defined palladium–BIAN–NHC chloro dimer: Highly efficient N-Heterocyclic carbene (NHC) catalyst platform for Buchwald–Hartwig C–N cross-coupling reactions

Buchwald-Hartwig amination has become the fundamental method for constructing molecular architectures throughout chemical research, including the synthesis of pharmaceutical agents, natural products, fine chemicals, and advanced materials. Herein, we report air-stable, well-defined palladium–BIAN–NHC chloro dimer, [Pd(BIAN–NHC)(μ-Cl)Cl]2, for Buchwald-Hartwig C–N cross-coupling reactions of aryl halides. This rapidly activating catalyst framework merges the reactive properties of palladium chloro dimers, [Pd(NHC)(μ-Cl)Cl]2, with the structural features of acenaphthoimidazol-2-ylidenes. [Pd(BIAN–NHC)(μ-Cl)Cl]2 is the most reactive Pd(II)–NHC precatalyst to date, undergoing fast activation under both inert atmosphere and aerobic conditions. The catalyst shows an excellent reactivity in Buchwald-Hartwig amination of aryl halides (59 examples), including challenging substrates, diamination and direct functionalization of pharmaceuticals. The steric protection enables high reactivity under both inert atmosphere and aerobic conditions. [Pd(BIAN–IPr)(μ-Cl)Cl]2 should be routinely utilized for the synthesis of C–N bonds to make valuable amines, where it replaces the most commonly deployed at present IPr (IPr = 1,3-bis(2,6-isopropyl)imidazol-2-ylidene).

N-heterocyclic carbene-catalyzed atroposelective synthesis of N-Aryl phthalimides and maleimides via activation of carboxylic acids

Traditionally, N-aryl phthalimides are synthesized by the condensation of phthalic anhydride and aniline derivatives, usually proceeding under harsh conditions. The alternative mild and organocatalytic strategies for their synthesis are underdeveloped. Herein, we demonstrate the organocatalytic atroposelective synthesis of N-aryl phthalimides via the traditional N-CC=O disconnection under mild conditions. The in-situ acid activation of phthalamic acid and subsequent N-heterocyclic carbene (NHC)-catalyzed atroposelective amidation allowed the synthesis of well-decorated N-aryl phthalimides in excellent yields and enantioselectivities. Mechanistic studies reveal the addition of NHC to the in situ generated isoimides, thus introducing a unique mode of generating acylazoliums. Interestingly, both enantiomers of the product can be accessed from the same phthalic anhydride and aniline using the same NHC pre-catalyst. Moreover, this strategy has been extended to the atroposelective synthesis of N-aryl maleimides.

(NHC)Pd(OAc)2]: Highly Active Carboxylate Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalysts for Suzuki-Miyaura and Buchwald-Hartwig Cross-Coupling of Amides by N-C(O) Activation.

In the past eight years, the selective cross-coupling of amides by N-C(O) bond activation has emerged as a highly attractive manifold for the manipulation of traditionally unreactive amide bonds. In this Special Issue on Next-Generation Cross-Coupling Chemistry, we report the Suzuki-Miyaura and Buchwald-Hartwig cross-coupling of amides by selective N-C(O) cleavage catalyzed by bench-stable, well-defined carboxylate Pd(II)-NHC (NHC = N-heterocyclic carbene) catalysts {[(NHC)Pd(O2CR)2]}. This class of Pd(II)-NHCs promotes cross-coupling under exceedingly mild room-temperature conditions owing to the facile dissociation of the carboxylate ligands to form the active complex. These readily accessible Pd(II)-NHC precatalysts show excellent functional group tolerance and are compatible with a broad range of amide activating groups. Considering the mild conditions for the cross-coupling and the facile access to carboxylate Pd(II)-NHC complexes, we anticipate that this class of bench-stable complexes will find wide application in the activation of amide N-C(O) and related acyl X-C(O) bonds.

Telomerization of butadiene with ethanol mediated by palladium N-heterocyclic carbene catalysts

The telomerization reaction of dienes with alcohols mediated by organopalladium complexes represents a versatile method to convert butadiene into value-added chemicals. In this contribution, we have examined the catalytic behavior of a series of well-defined palladium N-heterocyclic carbene precatalysts (Pd-NHC) in the telomerization of butadiene with ethanol. The bulky and less sterically demanding NHC ligands greatly influence yields and selectivity towards the linear product. With more hindered NHC ligands, the branched product is obtained in unprecedented higher amounts. The telomerization of butadiene with the renewable solketal leads to selective and complete conversion to product in minutes.

Palladium N-Heterocyclic Carbene Pre-catalysts Bearing Different Ancillary Ligands for the Buchwald–Hartwig Amination of Cyclic Secondary Amines with Aryl Chlorides

Palladium N-Heterocyclic Carbene Pre-catalysts Bearing Different Ancillary Ligands for the Buchwald–Hartwig Amination of Cyclic Secondary Amines with Aryl Chlorides

IPr#-PEPPSI]: A Well-Defined, Highly Hindered and Broadly Applicable Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalyst for Cross-Coupling Reactions.

In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr#-PEPPSI], a new, well-defined, highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#-PEPPSI] in cross-coupling reactions in a range of bond activations with C-N, C-O, C-Cl, C-Br, C-S and C-H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#-PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)-NHC precatalysts in chemistry research.

Asymmetric redox benzylation of enals enabled by NHC/Ru cooperative catalysis

The development of general methods for asymmetric benzylation of prochiral carbon nucleophiles remains a challenge in organic synthesis. The merging of ruthenium catalysis and N-heterocyclic carbene (NHC) catalysis for asymmetric redox benzylation of enals has been achieved, which opens up strategic opportunities for the asymmetric benzylation reactions. A wide range of 3,3'-disubstituted oxindoles with a stereogenic quaternary carbon center widely existing in natural products and biologically interesting molecules is successfully obtained with excellent enantioselectivities [up to 99% enantiomeric excess (ee)]. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of oxindole skeletons. Furthermore, the linear correlation between ee values of NHC precatalyst and the product elucidated the independent catalytic cycle of either the NHC catalyst or the ruthenium complex.

Suzuki–Miyaura Cross-Coupling of 2-Pyridyl Trimethylammonium Salts by N–C Activation Catalyzed by Air- and Moisture-Stable Pd–NHC Precatalysts: Application to the Discovery of Agrochemicals

We report the first Suzuki-Miyaura cross-coupling of 2-pyridyl ammonium salts by highly selective N-C activation catalyzed by air- and moisture-stable Pd(II)-NHC (NHC = N-heterocyclic carbene) precatalysts. The use of well-defined and highly reactive [Pd(IPr)(3-CF3-An)Cl2] (An = aniline) or [Pd(IPr)(cin)Cl] (cin = cinnamyl) Pd(II)-NHC catalysts permits an exceptionally broad scope of the cross-coupling to furnish valuable biaryl and heterobiarylpyridines that are ubiquitous in medicinal chemistry and agrochemistry research. The overall process leverages the Chichibabin C-H amination of pyridines with N-C activation to enable an attractive strategy to the 2-pyridyl problem. The utility of the method to the discovery of potent agrochemicals is presented. Considering the importance of 2-pyridines and the versatility of N-C activation methods, we envision that this new C-H/N-C activation strategy will find broad application.

A General C-N Cross-Coupling to Synthesize Heteroaryl Amines Using a Palladacyclic N-Heterocyclic Carbene Precatalyst.

A new palladacyclic N-heterocyclic carbene precatalyst was designed by the combination of 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene (AnIPr) with an achiral 2-naphthyl-4,4-dimethyloxazoline palladacyclic fragment. Applying this precatalyst enabled a general protocol for Pd-catalyzed C-N cross-coupling reactions of challenging five- or six-membered ring heteroaryl chlorides and various heterocyclic amines. The desired aminated products, including commercial pharmaceuticals or key intermediates such as piribedil, cyprodinil, V600EBRAF inhibitor, tripelennamine, 517-β-hydroxysteroid dehydrogenase inhibitor, brexpiprazole, and sonidegib, were achieved in good to excellent yields (>61 examples, ≤99% yields).

N-Heterocyclic Carbene Triazolium Salts Containing Brominated Aromatic Motifs: Features and Synthetic Protocol.

In this work, we provide a brief overview of the role of N-aryl substituents on triazolium N-heterocyclic carbene (NHC) catalysis. This synopsis provides context for the disclosed synthetic protocol for new chiral N-heterocyclic carbene (NHC) triazolium salts with brominated aromatic motifs. Incorporating brominated aryl rings into NHC structures is challenging, probably due to the substantial steric and electronic influence these substituents exert throughout the synthetic protocol. However, these exact characteristics make it an interesting N-aryl substituent, because the electronic and steric diversity it offers could find broad use in organometallic- and organo-catalysis. Following the synthetic reaction by NMR guided the extensive modification of a known protocol to enable the preparation of these challenging NHC pre-catalysts.

Chemoselective Intermolecular Cross-Benzoin Reaction of Aliphatic Aldehydes and Isatins via N-Heterocyclic Carbene Catalysis

An N-heterocyclic carbene (NHC)-catalyzed chemoselective intermolecular cross-benzoin reaction of aliphatic aldehydes with isatins is developed, affording biologically important 3-substituted 3-hydroxyoxindoles (on gram scale) in moderate to good yields (46–90%). The employment of a morpholinone-derived pentafluorophenyl-substituted triazolium salt as the electron-deficient NHC pre-catalyst is essential to make the reaction go through the cross-benzoin reaction pathway rather than the hydroacylation reaction pathway.

Enantioselective N-Heterocyclic Carbene-Catalyzed Kinetic Resolution of Anilides.

The N-heterocyclic carbene (NHC)-catalyzed enantioselective kinetic resolution of anilides (a kind of hemiaminals) is reported. Upon exposure to the reaction in the presence of an NHC precatalyst and base, catalytic C-O bond formation occurs, providing axially chiral isoindolinones in high yields with excellent enantioselectivities.

Organocatalytic Cross-Coupling of Biofuranics to Multifunctional Difuranic C11 Building Blocks

To synthesize the still missing C11 furoins as potential trifunctional difuranic building blocks for biopolymers and biofuels, the route based on the cross-coupling of two biofuraldehydes, furfural (FF) and 5-hydroxymethylfurfural (HMF), has been investigated using organic N-heterocyclic carbene (NHC) catalysts. This NHC-catalyzed coupling reaction in solution gives a statistical mixture of products including homocoupled C10 and C12 furoins 1 and 4, as well as cross-coupled C11 furoins 2 and 3, regardless of the electronics or sterics of the NHC precatalyst used, but a slight preference for cross-coupled products (∼60% 2 + 3 combined) under neat conditions has been achieved. Cross-coupled products 2 and 3 have been isolated in 48.1% yield and further separated into their pure state in 22.2% and 19.9% yield for 2 and 3, respectively. The isolated 2 and 3 have been fully characterized by NMR, HRMS, and single crystal X-ray diffraction. A simple metal-free/in-air oxidation reaction converts these two isomeri...

ChemInform Abstract: Synthesis of 5,6‐Dihydro‐2H‐pyran‐2‐ones (Microreview)

AbstractReview: [19 refs.

Enantioselective benzoin condensation catalyzed by spirocyclic terpene-based N-heterocyclic carbenes

The synthesis of new chiral spirocyclic triazolium salts, derived from (1S)-fenchone and (1R)-camphorquinone, are described. These salts, which are N-heterocyclic carbene precatalysts, were successfully employed in the catalytic asymmetric benzoin condensation affording acyloins with good yields and moderate enantioselectivities.

Synthesis of 5,6-dihydro-2H-pyran-2-ones (microreview)

5,6-Dihydro-2H-pyran-2-ones constitute an important class of heterocyclic compounds which also may be considered as α,β-unsaturated δ-lactones. These types of heterocycles have shown a wide range of biological and pharmacological activities including human antitumor,1 , 2 antifungal,3 , 5 antimicrobial,4 anti-inflammatory,4 antistress,4 antibiotic,5antituberculosis,6 antiparasitic,6 antiviral;7 5,6-dihydro-2Hpyran-2-ones are also known as the inducer of a colony stimulating factor in bone marrow stromal cells.5 All this made 5,6-dihydro-2H-pyran-2-ones more attractive both for chemists and pharmacologists. For example, (R)-rugulactone which was firstly reported in 2009 by Cardellina and coworkers possess interesting anticancer properties.2 In addition, 5,6-dihydro-2H-pyran-2-ones as chemical intermediates have widely been applied to the synthesis of numerous organic compounds including heterocycles.8 Nowadays, there are several synthetic routes to the preparation of these heterocycles including intramolecular cyclization, N-heterocyclic carbeneprecatalyst (NHC-precatalyst) reaction of enals and ketones, dicobaltoctacarbonyl-mediated tandem (5+1)/(4+2) cycloaddition, ring-closing metathesis of dienes containing carboxylate group by Grubbs II catalyst, (3+2) cycloaddition reaction, condensation reaction, and biosynthesis pathway.

α-Fluoroallenoate Synthesis via N-Heterocyclic Carbene-Catalyzed Fluorination Reaction of Alkynals.

The first catalytic α-fluoroallenoate synthesis is described. With a suitable combination of N-heterocyclic carbene precatalyst, base, and fluorine reagent, the reaction proceeded smoothly to yield a wide range of α-fluoroallenoates with excellent chemoselectivity. These substituted α-fluorinated allenoates have been synthesized for the first time, and they are versatile synthetic intermediates toward other useful fluorine-containing building blocks.

Palladium N-Heterocyclic Carbene Precatalyst Site Isolated in the Core of a Star Polymer.

An approach for supporting a Pd-NHC complex on a soluble star polymer with nanoscale dimensions is described. The resulting star polymer catalyst exhibits excellent activity in cross-coupling reactions, is stable in air and moisture, and is easily recoverable and recyclable. These properties are distinct and unattainable with the small-molecule version of the same catalyst.

Photoswitchable NHC-promoted ring-opening polymerizations

The UV-induced photocyclization of a dithienylethene-annulated N-heterocyclic carbene precatalyst enabled photoswitchable ring-opening polymerizations of ε-caprolactone and δ-valerolactone. The polymerizations proceeded efficiently in ambient light, however UV irradiation attenuated the reaction rate (k(amb)/k(UV) = 59). Subsequent visible light exposure reversed the photocyclization and restored catalytic activity.

Design and synthesis of novel chiral dihydroimidazolium cyclophanes as N-heterocyclic carbene precatalysts

A series of novel diphenyl ethylenediamine (DPEN) derived C2 symmetric dihydroimidazolium cyclophanes were designed and synthesized as organo NHC precatalysts. The resultant organo NHC-catalyzed reactions with superior enantioselectivity than traditional C2 dihydroimidazolidine NHCs as exemplified by NHC-catalyzed asymmetric intramolecular Stetter reactions.